Topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment-resistant strains of head lice

ABSTRACT

An avermectin-based topical formulation is disclosed which is useful for prevention and treatment of head lice ( Pediculus humanus capitis ). This topical formulation may be formulated as a shampoo-condition which comprises an effective amount of avermectin, solubilizers, suspending agents, preservatives, non-ionic surfactants, humectants, a silicone compound, and water. Also disclosed are methods of using the topical formulations disclosed within this specification to treat either a susceptible or treatment-resistant strain of lice, as well as uses in the manufacture of a medicament for treating or preventing a lice infestation from a susceptible or treatment-resistant strain in a human patient.

RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) of U.S.patent application 60/851,352 filed Oct. 12, 2006 and U.S. patentapplication 60/976,259 filed Sep. 28, 2007, each of which areincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to topical formulations containingavermectin for use in the prophylactic and therapeutic treatment of ahead lice infestation in humans. The topical formulations of the presentinvention are effective against both susceptible and treatment resistantstrains of head lice. To this end, the present invention also relates tomethods of treating an infestation of head lice which comprisesadministering one or multiple doses of the disclosed topicalformulations to a human patient, wherein the infestation being treatedrepresents a susceptible and/or treatment-resistant strain of head lice.

BACKGROUND OF THE INVENTION

Head lice, Pediculus humanus capitis, are parasitic insects that mainlylive and feed in the scalp and neck hairs of human hosts. A typicalinfested scalp of a patient with head lice houses about 20 female lice,which are prolific egg layers over the course of their 30-day lifecycle. These eggs are cemented to the hair shaft and are commonly callednits. Head lice have a similar appearance to wingless ants. Like allinsects, the parasite has a body that is constructed of a hard chitinousexoskeleton. The egg case that surrounds the nits is of similarconstruction and is glued to the hair shaft via a cement that is similarin characteristics to the hair keratin itself. Infections, irritationand lesions to the scalp are common side effects of head liceinfestation. Head lice infestation is an oft occurring problem in theUnited States and is easily spread from direct head-to-head contact withan infected person's hair and common usage of combs and clothing. Thereare between 6 to 12 million annual head lice infestations in the UnitedStates. Grade school children suffer most from head lice infestations,with one result being an accumulation of absences from school, wherelice outbreaks are believed to account for 12 million to 24 millionmissed days a year. A majority of public schools have instituted a nolice or a no lice and no-nit policy, forcing absenteeism on children andmaybe forcing working parents to stay at home to look after them. For areview, see Burkhart and Burkhart (2006, Expert Opin. Drug Saf.5(1):169-179).

Treatment for eliminating head lice traditionally included home remediessuch as smearing mayonnaise, olive oil, a hair pomade, or some heavilyviscous material about an infested scalp coupled with rigorous combingof the hair and meticulous removal of adult lice, nymphs, and nits.Though these home remedies do not kill head lice, the prevailing thoughtis that the viscosity of the material makes it hard for head lice toroam about the scalp, making for easy removal. Such home remedies areusually ineffective at controlling head lice due to the ability of thelice to revive rapidly once these materials are removed.

More effective treatments for eliminating head lice involve massagingthe infested scalp with over-the-counter (OTC) topical creams containingactive insecticides. Because of their potential toxicity to the humanhost, the use of these topical formulas are regulated by the FDA.Over-the-counter insecticides typically have pyrethrins or permethrin asactive ingredients.

Pyrethrins are any one of six naturally occurring insecticides extractedfrom the chrysanthemum flower. Along with its synthetic derivative,permethrin, these molecules act on susceptible head lice by increasingsodium levels in the nervous system of the lice. The increased sodiumlevels cause membrane depolarization in the nervous system of the headlice, which eventually leads to spastic paralysis and death of the headlice.

When first introduced, both pyrethrin and permethrin were highlyeffective at eliminating susceptible lice. In the late 1980's, variousformulations of both active ingredients had a high efficacy foreliminating adult head lice and their nits. However, recent reportsindicate that treatment-resistant strains of head lice have evolved forNix®, having 1% permethrin as an active ingredient, and various Rid®products, having approximately 0.33% pyrethrin as active ingredients. Itcomes as no surprise that strains of treatment-resistant head lice havebeen identified in both the United States and Europe due to the similarkilling pathway for both insecticides.

Prescription products are also currently available and contain eitherlindane or malathion as the active ingredient. These insecticidesspecifically target the nervous system of the head lice. The chlorinatedhydrocarbon, lindane, is formulated as a topical shampoo and isprescribed to treat head lice infestations. Lindane eliminates head liceby effectively slowing the insect's central nervous system causingparalysis and eventual death.

The reports of continued effectiveness of lindane for eliminating headlice is inconsistent at best. Reports on the efficacy of lindane fortreating head lice have been listed from 17% in the U.S. to as high as61% and 93% in other parts of the world. However, treating head licewith lindane poses problems for the human host. Side effects includetoxicity to the central nervous system, convulsions, seizures; and itmay be a carcinogen. Lindane has also been reported to have a slowkilling time, and has poor ovicidal capacities.

Malathion is also available as a prescription insecticide to treat headlice infestations (e.g., OVIDE® an alcohol based lotion containing 0.5%malathion, terpeneol, dipentene and pine needle oil in 78% isopropylalcohol). It is an organophospate that causes spastic paralysis anddeath in head lice.

As noted above, recently there has been an increase in strains of headlice which show resistance to available OTC and prescription treatmentsfor head lice infestation. These parasites have adapted to chemicaltreatments using pyrethrins, permethrins, lindane, and malathion. In theUS, permethrin resistant lice have been found in Massachusetts, Idaho,Texas, California and Florida. Single and dual resistance topyrethrins/permethrins and malathion has been broadly reported in GreatBritain (see Downs et al., 1999, Br. J. Dermatology 141:508-511).

Strains of head lice have been identified worldwide which are resistantto all currently available topical treatments. Possible neural damage tothe human host prevents raising the insecticide levels above the currentthreshold in an attempt to combat these newer treatment-resistant headlice. One possible way to address this alarming increase in treatmentresistant head lice would be to develop and introduce a topicalpediculicide formulation which is (i) safe; (ii) effective against headlice infestation from both susceptible and treatment-resistant strains;(iii) is convenient for patient use; and, (iv) has not previously beenmarketed for such an indication. Such a strategy is disclosed herein byutilizing an anthelmintic agents derived from avermectin.

Avermectin is a natural fermentation product derived from the soilbacterium Streptomyces avermitilis. Avermectin naturally occurs asabamectin, a mixture of avermectin isomers containing >80% avermectinB_(1a) and <20% avermectin B_(1b), see FIGS. 1A and 1B, respectively.Other semi-synthetic forms of avermectin and mutated forms ofStreptomyces avermitilis containing avermectin, for example doramectin,ivermectin, selamectin, and eprinomectin have found medicinal uses aswell.

Ivermectin is the synthetic dihydro form of avermectin and is aneffective insecticide. These compounds have been shown to selectivelybind with high affinity to glutamate-gated chloride ion channels (GluClchannels) as well as γ-aminobutyric acid (GABA) receptors, thus blockingthe chemical transmission across the nerve synapses which utilizeglutamate and GABA, respectively. This blockage, which occurs ininvertebrate nerve and muscle cells, leads to an increase in thepermeability of the cell membrane to chloride ions withhyperpolarization of the nerve or muscle cell, resulting in paralysisand death of the parasite.

The selectivity of ivermectin is attributable to the fact that somemammals do not have glutamate gated chloride channels and that thecompound has a low affinity for mammalian ligand-gated chloridechannels. In addition, ivermectin does not readily cross the blood brainbarrier in humans. Thus, ivermectin has a documented history of highlysafe and efficacious use in humans and animals. For example, over 400million doses of orally formulated ivermectin have been used forcontrolling river blindness since 1986.

Ivermectin is commercially available as STROMECTOL® for eradication ofStrongyloides stercoralis, which causes strongyloidiasis, and Onchocercavolvulus, which causes onchocerciasis. Ivermectin is also available asMECTIZAN® for eradication of Onchocerca volvulus and Wuchereriabancrofti. Ivermectin is usually available as a mixture containing atleast 90% 5-O-demethyl-22,23-dihydroavermectin A_(1a) and less than 10%5-O-demethyl-25-de(1-methylpropyl)-22,23-dihyro-25-(1-methylethyl)avermectin A_(1a), generally referred to as 22,23-dihydroavermectinB_(1a) and B_(1b), or H₂B_(1a) and H₂ B_(1b), respectively, see FIG. 2Aand FIG. 2B respectively.

Glaziou et al. (1994, Trop. Med. Parasitol. 45: 253-254) disclosetreating humans with a single oral 200 ug/kg dose (n=26). Oralivermectin was effective at this concentration against head lice. Asecond dose was suggested for prophylaxis, but not as part of theinitial therapeutic regime.

Youssef et al. (1995, Amer. J. Trop. Med. Hyg. 53(6):652-653) describe amethod of topical application of ivermectin to treat head lice.

Dunne et al. (1991, Trans. R. Soc. Trop. Med. Hyg. 85: 550-551) discloseresults from a study wherein ivermectin was administered as a singleoral dose of 100-200 ug/kg to treat head lice infestation. Positive, butnot absolute, results where reported for this oral dosing regime.

U.S. Pat. No. 4,199,569, issued Apr. 23, 1980, discloses ivermectin,which as noted above is a semisynthetic, anthelmintic agent derived fromthe avermectins, a class of highly active broad-spectrum anti-parasiticagents isolated from the fermentation products of Streptomycesavermitilis.

U.S. Pat. No. 6,103,248, issued to Burkhart and Burkhart, disclose atopical formulation for the treatment of head lice which includes akilling agent, and a lipophilic carrier having a viscosity within arange of from about 10, 000 centipoise to about 85,000 centipoise at 21°C.

U.S. Pat. No. 6,524,602, also issued to Burkhart and Burkhart, disclosea topical formulation which includes a parasiticide andN,O-carboxymethyl-chitosan polymer, and a vehicle for the parasiticideand polymer.

U.S. Pat. No. 7,064,108, issued to Guzzo, et al., discloses anivermectin-based topical gel composition comprising a pharmaceuticallyacceptable alcohol (30-40%; e.g., propylene glycol), a pharmaceuticallyacceptable glycol (30-40%; e.g., ethyl alcohol), and a pharmaceuticallyacceptable carrier. Ivermectin is contemplated at a w/v basis from 0.005to 1.0%. Additional additives may include d-limonene, a nonionicsurfactant and a pharmaceutically acceptable viscosifying agent (e.g.,hydroxypropylcellulose).

U.S. Pat. No. 5,952,372, issued to William McDaniel, discloses methodsof treating rosacea in humans involving orally-administered ortopically-applied ivermectin. The topical aspect of the inventionsuggests a topical formulation with about 2% ivermectin.

U.S. Pat. Nos. 6,399,652; 6,399,651 and 6,319,945, issued to L. DeanParks, disclose methods of treating skin disorders via application oftopical formulations containing ivermectin to treat acne vulgaris (the'652 patent), a variety of dermatoses (e.g., transient acantholyticdermatitis, acne miliaris necrotica, acne varioliformis, perioraldermatitis, and acneiform eruptions; the '651 patent) and seborrheicdermatitis (the '945 patent).

U.S. Pat. No. 6,262,031, issued to Larouche, et al. discloses an oralformulation of ivermectin to treat a head lice infestation.

It is evident that the OTC or prescription products presently availableto the public for treatment or prevention of head lice each have theirown significant drawbacks. Over-the-counter products such as pyrethrinand permethrin are presently compromised due to emerging strains oftreatment-resistant head lice. On the other hand, the prescriptionproducts such as lindane and malathion carry recognized health risks andare also losing effectiveness due to the emergence oftreatment-resistant lice. To this end, there remains a need for apatient friendly product that is safe and effective in treatingsusceptible and/or treatment-resistant head lice. The present inventionaddresses and meets this needs by disclosing an avermectin-based topicalformulation and exemplifying an ivermectin-based topical formulation,and associated methods of use, which is safe, will appeal to the patientfor ease of use and is shown to be effective against multiple strains ofeither susceptible and treatment-resistant head lice.

SUMMARY OF THE INVENTION

The present invention relates to a topical formulation for use in theprophylaxis or elimination of head lice (Pediculus humanus capitis) on ahuman host, wherein the formulation comprises a pharmaceuticallyeffective amount of an avermectin compound, solubilizers, suspendingagents, preservatives, non-ionic surfactants, humectants, and water.

The present invention also relates to a topical formulation for use inthe prophylaxis or elimination of head lice (Pediculus humanus capitis)on a human host, wherein the formulation comprises a pharmaceuticallyeffective amount of ivermectin, solubilizers, suspending agents,preservatives, non-ionic surfactants, humectants, and water.

In additional embodiments of the present invention, the topicalavermectin/ivermectin-containing formulation may further compriseadditional beneficial agents; non-limiting examples being nutrients andvitamins, and the absence of pharmaceutically accepted glycols.

The present invention relates to a method of treating a head liceinfestation in a human patient which comprises topically administeringto the patient an avermectin- or ivermectin-based formulation via one ormultiple doses; the strain of head lice being either a susceptiblestrain, a treatment-resistant strain, or any combination of either orboth types of strains within a specific human infestation.

The present invention also relates to a method of treating a head liceinfestation in a human patient which comprises topically administeringto the patient an avermectin- or an ivermectin-based formulation asdisclosed herein by one dose or multiple doses; the strain of head licebeing either a susceptible strain or a treatment-resistant strain or anycombination of either or both types of strains within a specific humaninfestation.

Another aspect of the present invention relates to the use, inmanufacture of a topical medicament for treating or preventing a headlice infestation from a treatment-resistant strain in a human patient,of avermectin or ivermectin.

Another aspect of the present invention relates to the use, in themanufacture of a medicament for treating or preventing a head liceinfestation from a susceptible or treatment-resistant strain in a humanpatient, of a topical formulation according to the present invention.

The present invention further relates to a method of preventing a headlice infestation in a human patient at risk which comprises topicallyadministering to the human an avermectin- or an ivermectin-basedformulation as disclosed herein by one dose or multiple doses(preferably a single application) so as to prevent infestation in thepatient at risk (i.e., a human likely to be in close contact with aninfected individual) to a strain of head lice being either a susceptiblestrain or a treatment-resistant strain or any combination of either orboth types of strains within a specific human infestation.

Therefore, the present invention relates to a method of eliminating orpreventing an infestation of head lice on a human patient, whether theinfecting head lice strain be a susceptible strain or a treatmentresistant strain, which comprises applying one or multiple doses(applications) of the topical avermectin-containing formulation,including but not limited to an exemplified ivermectin-containingformulation, to the individual for a length of time to allowbiologically effective contact between the active ingredient and thelice.

The present invention also relates to an avermectin- or ivermectin-basedformulations which is effective against pediculosis via pubic lice(Phthirus pubis) and body lice (Pediculus humanis corporis). Theformulations of the present invention may be used ‘as is’ to treat apubic lice and/or body lice infestation, or may be altered to providefor a formulation with the consistency of a cream rinse or lotion thatmay be applied to the affected area(s), left on for a period of time ascontemplated herein for treatment of head lice, and then rinsed off.Multiple dosing may also occur as contemplated herein for treating headlice with a formulation as disclosed herein.

Another aspect of the present invention relates to the use, inmanufacture of a topical medicament for treating or preventing a pubiclice or body lice infestation from a treatment-resistant strain in ahuman patient, of avermectin or ivermectin.

Another aspect of the present invention relates to the use, in themanufacture of a medicament for treating or preventing a pubic lice orbody lice infestation from a susceptible or treatment-resistant strainin a human patient, of a topical formulation according to the presentinvention.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B show the chemical structures of avermectin, form B_(1a)(1A) and B_(1b) (1B).

FIGS. 2A and 2B show the chemical structure for ivermectin, form B_(1a)(2A) and B_(1b) (2B).

FIG. 3 shows log time versus percent mortality of permethrin-resistanthuman head lice from the South Florida (SF-HL) strain following a 10minute exposure to 1%, 0.5%, and 0.25% ivermectin formulations.

FIG. 4 shows log time versus percent mortality of permethrin-resistanthuman head lice from the South Florida (SF-HL) strain treated with a0.5% ivermectin formulation for 3 minutes, 5 minutes, and 10 minutes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an avermectin-containing topicalformulation useful as a pediculicidal agent in the treatment orprevention of an infestation of head lice, where the infested lice maybe either a susceptible or treatment-resistant strain of Pediculushumanus capitis.

One embodiment of the present invention relates to anivermectin-containing topical formulation useful as a pediculicidalagent in the treatment or prevention of an infestation of head lice,particularly where the infested lice may be either a susceptible ortreatment-resistant strain of Pediculus humanus capitis.

The avermectin/ivermectin-based formulations of the present inventionaddress the emerging problem of treatment-resistant head lice strains byallowing use of a single product which is active in eliminating orpreventing head lice infestations, whether the infestation represents asusceptible or treatment-resistant strain of head lice.

A portion of the current invention is exemplified by an ivermectin-basedformulation in an assay to determine killing ability againstpermethrin-resistant head lice. It is well known in the art that similartreatment regimes are presently utilized to treat not only a head liceinfestation, but also at least an infestation of pubic lice or bodylice. Thus, it will be evident that avermectin- or ivermectin-basedformulations will be effective in treating not only head lice, but alsoinfestations of the human body of pubic lice and body lice. Pubic lice(Phthirus pubis, e.g., “crabs”) are usually found in the pubic area butmay also be found on facial hair, on eyelashes, on eyebrows, in thearmpits, on chest hair, and, rarely, on the scalp.

Body lice (Pediculus humanis corporis) live and lay eggs in the seams ofclothing. The lice are only present on the body when they feed. Undersome conditions, these lice may transmit diseases such as typhus,relapsing fever, and trench fever. The formulations of the presentinvention may be used ‘as is’ to treat a pubic lice and/or body liceinfestation. Of course, the core components of the disclosed formulationmay be altered to provide for a formulation with the consistency of acream rinse or lotion that may be applied to the affected area(s), lefton for a period of time as contemplated for treatment of head lice, andthen rinsed off. Multiple dosing may also occur as contemplated hereinfor treating head lice with a formulation as disclosed herein.

The present invention also relates to a method of treating or preventinga head lice infestation, whether the infestation be from a strain ofhead lice that remains susceptible to current OTC and prescriptionpediculicides (“a susceptible strain”) or from a strain that isresistant to one or more available OTC and/or prescription formulations(“a treatment-resistant” or “drug-resistant” strain). Thus, one aspectof the invention relates to a method of treatment or prevention of aninfestation of head lice on a human patient utilizing an avermectin- orivermectin-based formulation, whether the infecting head lice strain maybe a susceptible strain or a treatment-resistant strain.

This methodology comprises applying one dose or multiple doses(applications) of the topical avermectin- or ivermectin-containingformulation to the individual for a length of time to allow an effectiveamount of the active ingredient to contact the infecting lice.

An additional aspect of this portion of the invention relates to amethod for prophylaxis or elimination of either susceptible ortreatment-resistant head lice using the avermectin-containingformulation as a shampoo-conditioner, where the shampoo-conditioner isused twice during about a seven day period (day 1 and day 7), left onthe scalp for 1 to 60 minutes at each application, and then rinsed withwarm water. The shampoo-conditioner is formulated to leave the hair ingood condition while ridding the scalp of lice.

Thus, another aspect of the present invention relates to the use, inmanufacture of a topical medicament for treating or preventing a headlice, pubic lice or body lice infestation from a treatment-resistantstrain in a human patient, of avermectin or ivermectin. Another aspectof the present invention relates to the use, in the manufacture of amedicament for treating or preventing a pubic lice or body liceinfestation from a susceptible or treatment-resistant strain in a humanpatient, of a topical formulation according to the various formulationsdisclosed herein.

One central aspect of the present invention is that the topicalformulation will comprise avermectin. Avermectin may be present atvarying concentrations, with an expected range (at a weight/volumepercentage) of from 0.005% to 5.0% (w/v) [i.e., a 1% avermectinformulation would include 1 gram (g) avermectin per 100 milliliters (ml)(1 g/100 ml)] of formulation volume.

Another contemplated range for an avermectin concentration would be fromabout 0.1% to about 2.0% (w/v), which is further supported in Example 1,where avermectin, in the form of ivermectin, concentrations of 0.25%,0.5% and 1.0% were shown to promote effective killing of apermethrin-resistant strain of head lice.

Of course, dosing may be varied either by the altering the avermectinconcentration, as noted above, or by increasing the amount of topicalformulation applied to the scalp of the human patient. It will beevident upon review of this specification, that while anivermectin-based formulation is exemplified herein, other knownavermectins beside ivermectin are also contemplated as the activeingredient which will be useful to practice the present invention.

While dosing ranges may vary, it is expected that a single application(dosage) of an exemplified ivermectin-containing formulation of thepresent invention would be in the range from about 1 ml to about 100 ml;with an additional range being from about 3 ml to about 75 ml.

In a single embodiment, at least about 60 ml the topical formulation isapplied to totally saturate the roots and to effectively cover theentire scalp area. It is evident upon review of this specification thatthe artisan may vary the ivermectin concentration and/or volume of thetopical formulation to manipulate the effective amount of ivermectin tobe delivered to the patient's scalp.

Another aspect of the present invention, as noted above, relates tomultiple doses of the topical avermectin- or ivermectin-basedformulations of the present invention. Multiple applications willinclude at least one, two, three or four additional dosages beyond theinitial dose, with one or possibly two additional doses being mostreasonably contemplated.

The initial dose is most likely in response to an infestation of headlice, while the additional subsequent dose(s) are follow up applicationsto eradicate lice that hatch following the first dose or lice that havesomehow survived the first dosing. Multiple dosing for a therapeuticregime provides an opportunity to deliver greater amounts of avermectinspaced over a determined time frame.

One aspect of this portion of the invention relates to a method forprophylaxis or elimination of either susceptible or treatment-resistanthead lice using the avermectin- or ivermectin containing formulation asa shampoo-conditioner. The shampoo-conditioner may be used twice duringabout a seven day period (day 1 and between about day 5 and day 9), aswell as three or four times (with an initial application on day 1followed for a second, third or fourth application at intervals fromabout 5 days to about 9 days). At each dosing, the formulation remainsin the scalp for from about 1 minute to 60 minutes or from about 3minutes to about 60 minutes, then rinsed with warm water.

The shampoo-conditioner is formulated to leave the hair in goodcondition while ridding the scalp of lice. Therefore, the presentinvention relates to a method of treating a head lice infestation in ahuman patient which comprises topically administering to the human aformulation as disclosed herein by one dose or multiple doses; thestrain of head lice being either a susceptible strain or atreatment-resistant strain.

Furthermore, the present invention relates to a method of preventing ahead lice infestation in a human patient at risk which comprisestopically administering to the human a formulation as disclosed hereinby one dose or multiple doses (preferably a single application) so as toprevent infestation in the patient at risk to a strain of head licebeing either a susceptible strain or a treatment-resistant strain. Thus,methods of the present invention are useful for preventing head liceinfestation in a human susceptible to such infestation.

Such an at risk individual would be a human coming into close contactwith an infested individual, such as a family member or possibly inresponse to an outbreak within a confined space such as school or theworkplace. Either a single or multiple dosing regime will be effective,the course of a prophylactic treatment most likely determined by theseverity of the outbreak.

Thus, the present invention provides a formula for prophylaxis andelimination of head lice comprising an effective amount of ivermectin ina shampoo-conditioner. However, the formula may be delivered in variousforms, non-limiting examples being creams, gels, pomades, and the like.The invention also provides a method for prophylaxis and elimination ofhead lice on human hosts comprising topically massaging said formula ina suitable carrier onto and about the infected area.

For the purposes of this invention, the following non-limitingdefinitions are used:

The term “active ingredient”, when directed toward the presentinvention, refers to an avermectin, including but not limited itssynthetic derivative, ivermectin. Ivermectin may be utilized as amixture of over 80% 22,23-dihydroavermectin B_(1a) and less than 20%22,23-dihydroavermectin B_(1b). As exemplified herein, ivermectin is amixture of at least 90% 22,23-dihydroavermectin B_(1a) and less than 10%22,23-dihydroavermectin B_(1b).

The terms “solubilizer” and/or “solubilizer phase” refers to compound ormixture of compounds in which the ivermectin is initially dissolved. Thesolubilizer phase is preferably a mixture of water miscible organiccompounds. By way of example, solubilizers may include the surfactantspolysorbate 80 and cetyl acetate or other surfactants as more fullydescribed herein.

The term “suspending agent(s)” refers to organic compounds that suspendthe pre-dissolved ivermectin before being dispersed in water. Suspendingagents include, without limitation, olive oil, shea butter, coco butter,vegetable oil, and the like.

The term “preservative(s)” refers to compounds that reduce the growth offungus and other bacterial agents. In one embodiment, preservatives areselected from the compounds in the paraben family.

The term “non-ionic surfactant(s)” refers to compounds which act at thewater-air and water-oil interfaces, thereby enhancing wetting ability,emulsion stabilization, foaming, rheology, antistatic, lubricity, andsurface conditioning properties of the shampoo-conditioner.

The term “emollient(s)” refers to compounds that soften and makes theskin smooth by preventing skin from loosing moisture.

The term “silicone compound” refers to hair conditioning agents thatchange the texture, feel, and appearance of human hair. In oneembodiment, the silicone compound is cyclomethicone.

The term “susceptible” or “susceptible strain” refers to a strain ofhead lice which is susceptible to one or more available OTC and/orprescription pediculicides, having active ingredients selected from thegroup consisting of pyrethrins, permethrins, lindane, and malathionwhere the active ingredient is at least at the pharmaceuticallyacceptable treatment concentration allowable for that respectivepediculicide(s) and all or effectively all head lice are killed at thatconcentration. In other words, a susceptible strain is a strain whichwill be effectively controlled following treatment with apharmaceutically acceptable concentration for that respectivepediculicide.

The term “treatment-resistant” or “drug-resistant” or any such similarterm refers to a strain of head lice which shows resistance to one ormore available OTC and/or prescription pediculicides having activeingredients selected from the group including, but not limited to one ormore pyrethrins, permethrin, lindane, and malathion, where the activeingredient is at least at the pharmaceutically acceptable treatmentconcentration recommended or allowed for that respective pediculicide(s)and at least some head lice survive at that concentration. Pyrethrinswhich are approved for use on humans are extracted from the chrysanthumflower, of which there are six active constituents which are esters oftwo carboxylic acids (chrysanthemic acid and pyrethric acid) and fourcyclopentenoles (pyrethrolone, cinerolone, and jasmolone I and II). So,it is evident that a treatment-resistant strain of lice is a strain thatshows a measurable level of resistance to killing by a specificpediculicide treatment regime as compared to a susceptible strain, whereall or effectively all of the head lice will be killed. Such a measuremay be made by an art-accepted assay, for example, as disclosed hereinin Example section 1; or may possibly be determined by other means(e.g., comparative testing in individuals).

The present invention is exemplified by, but in no way limited to, atopical ivermectin-containing formulation as disclosed in Table 1. Thisfinal formulation is in the consistency of a shampoo-condition and atleast comprises an effective amount of ivermectin, as well as asolubilising agent(s), water, a suspending agent(s), a surfactant(s),silicone compound(s), and a preservative(s), in any combination and/orconcentration which may be contemplated by the artisan upon review ofthis specification.

Solubilising Active Ingredient

FIGS. 1A and 1B show the chemical formula for avermectin, forms B_(1a)and B_(1b). FIGS. 2A and 2B show ivermectin as a mixture comprisingabout 90% 22,23-dihydroavermectin B_(1a) and less than about 10%22,23-dihydroavermectin B_(1b). Ivermectin may be delivered to a headlice infested scalp by way of an emulsion based shampoo-conditioner.However, ivermectin is hydrophobic and is poorly solvated by water.Thus, the active ingredient should preferably be pre-dissolved insuitable surfactants to improve the stability of said active ingredientsin water. Preferably, these surfactants are easily soluble in water orare water miscible.

In one embodiment, ivermectin is pre-dissolved in a mixture containingthe water miscible organic compounds, e.g. polysorbate 80, cetylacetate, and acetylated lanolin alcohol. More specifically, ivermectinis present in the formula at a level of about 0.05% to 5%, oralternatively from about 0.1% to 2% by weight, or alternatively fromabout 0.25% to 1% by weight. Polysorbate 80 is present in the formula ata level of about 5% to about 25% by weight, or alternatively from about10% to 15% by weight (e.g. about 11.25% to 13.5% by weight). Cetylacetate is present in the formula at a level of about 0.5% to 10% byweight, or alternatively from about 1% to 4% by weight (e.g. about 1.50%to 3.75% by weight). Acetylated lanolin alcohol is present in theformula at a level of about 0.10% to 3% by weight, or alternatively fromabout 0.5% to about 1% by weight (e.g, 0.15% to 0.75% by weight).

Having these surface active agents bound to the surfaces of ivermectinwill ensure that the active ingredient will be stable in the aqueousenvironment of the shampoo-conditioner. In one embodiment of theinvention ivermectin may be stabilized by pharmaceutically acceptedglycols present in said formula at a level below 30% by weight, such as,for example, below 25%, or below 20% or below 15% or below 10% or below5%. In another embodiment of the invention said formula does not includeany glycols.

Suspending Agents

Once the active ingredient is dissolved in a surfactant bath, ivermectinis placed in suspending agents. In one embodiment, a combination offatty oils and fats serve as suspending agents. Olive oil is atriacylglyceride, where three fatty acids are tethered to a glycerolbackbone and shea butter is primarily made of palmitic, stearic, oleic,linoleic, and arachidic fatty acids. Although these fatty acids haveshown to be adequate home remedies for removal of head lice from thescalp, they do not kill head lice. Both olive oil and shea butter areviscous materials that slow the movement of adult lice to better removethem. Also note that both fatty acids can act as skin moisturizers. Inone embodiment, olive oil is present in the formula at a level of about20% to 30% by weight, or alternatively from about 25% to 28% by weight(e.g., about 27.5% by weight). Shea butter is present in the formula ata level of about 1% to 5% by weight (e.g. about 2% by weight). Otherknown suspending agents which may be utilized in the formulations andrelated methods include, but are not limited to, coconut oil, palm oil,cottonseed oil, vegetable oil, soybean oil, olive oil, peanut oil, cornoil, sunflower oil, safflower oil, jojoba oil, canola oil, shea butter,cocoa butter, milk fat, amaranth oil, apricot oil, argan oil, avocadooil, babassu oil, ben oil, algaroba oil, coriander seed oil, false flaxoil, grape seed oil, hemp oil, kapok seed oil, meadowfoam seed oil, okraseed oil, perilla seed oil, poppyseed oil, prune kernel oil, pumpkinseed oil, quinoa oil ramtil oil, rice bran oil, camellia oil, thistleoil, wheat germ oil and combinations thereof.

Surfactants

The formulation may be further stabilized by non-ionic surfactants. Inone embodiment of the invention, a fatty alcohol or a mixture of fattyalcohols serve as surfactants. Apart from additional stabilization ofivermectin, the non-ionic surfactants have various purposes in thesurface chemistry of said formula, where said formula is used in a finalproduct comprising a shampoo-conditioner. In addition to theirsurface-active properties, fatty alcohols are emollients that make theskin smoother and act at the water-air and water-oil interfaces, therebyenhancing wetting ability, emulsion stabilization, foaming, rheology,antistatic, lubricity, and surface conditioning properties of theformula. Suitable non-ionic surfactants include, without limitations,oleyl alcohol, lanolin alcohol, sorbitan tristerate, bees wax, erucylalcohol, ricinolyl alcohol, arachidyl alcohol, capryl alcohol, capricalcohol, behenyl alcohol, lauryl alcohol, myristyl alcohol, cetylalcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, palmitoleylalcohol, linoleyl alcohol, elaidyl alcohol, elaidolinoleyl alcohol,linolenyl alcohol, elaidolinolenyl alcohol, glycerine, glyceryltriacetate, sorbitol, xylitol, maltitol, polydextrose, quillaia, lacticacid, urea, and combinations thereof.

In one embodiment of the invention, the fatty alcohols are oleyl alcoholand lanolin alcohol with combined concentration of about 10% to 35%, oralternatively about 18% to about 24% by weight. More specifically, oleylalcohol is present in the formula at a level of about 5% to 15% byweight (e.g. about 10% by weight). Lanolin alcohol is present in theformula at a level of about 3% to about 15% by weight, or alternativelyfrom about 5% to 10% by weight (e.g. about 8% by weight).

Sorbitan tristearate is available commercially as Glycomul® TS (Lonza,Inc.) or SPAN 65 as sold by Merck Schuchardt OHG. Sorbitan tristearateis a low HLB ester based surfactant and has many uses in the food andcosmetic industries. The chemical structure of sorbitan tristearate isdefined by a cyclic five member ether, with hydroxyl groups, and threefatty acid side chains. Sorbitan tristearate is present in the formulaat a level of about 0.1% to 3% by weight, e.g. about 0.5% by weight.

Silicone Compound

After ivermectin has been pre-dissolved and stabilized by surfactants, asilicone compound may be added. In one embodiment, the silicone compoundis selected from a group consisting of volatile silicones, of whichcyclomethicone is one. Cyclomethicone may act as a conditioner in theshampoo-conditioner. It gives a soft, silky feel to hair and evaporatesquickly leaving little residue. Cyclomethicone is present in the formulaat a level of about 1% to 5% by weight, e.g. about 3% by weight. Thus,conditioners which may be used include but are in no way limited tocyclomethicone, dimethicone, hexamethyldisiloxane,octamethyltrisiloxane, decamethyltetrasiloxane,dodecamethylpentasiloxane, polydimethylsiloxanes and combinationsthereof.

Preservatives

In yet another embodiment, the formula of the instant invention furthercontains a preservative, protecting the formula from fungus bychemicals. In one embodiment, the preservative is chosen from theparaben family. More specifically, the preservative is selected frommethylparaben, propylparaben, or a combination thereof. In oneembodiment, the concentration of the preservative is about 1% by weight.More specifically, methylparaben is present in the formula at levels ofabout 0.01% to 2% by weight (e.g. 0.20% by weight). Propylparaben ispresent in the formula at levels of about 0.01% to 1.0%, oralternatively from about 0.01% to about 0.5% by weight (e.g., 0.05% byweight). Also note that representative preservatives may include, butare not limited to, methylparaben, propylparaben, ethylparaben,butylparaben, isobutylparaben, isopropylparaben, benzylparaben and theirsodium salts thereof.

Water

The oil mixture containing pre-dissolved ivermectin, suspending agents,surfactants, a silicone compound and preservatives is then dispersed inwater. In one embodiment, water is deionized. Water acts as a carrierand may be included as warranted for any respective formulation. In theexemplified formulation, water is present in the formula at a level ofabout 30% to 40% by weight (e.g. 33% by weight). The addition of theoily mixture with ivermectin to deionized water results in a colloidalsuspension of ivermectin, where micelles form around the ivermectin andare arranged such that hydrophilic heads of the surfactants are incontact with the solvent water molecules and the hydrophobic tails ofthe surfactants are in contact with ivermectin. This formulation isespecially suitable delivering ivermectin in a shampoo-conditioner,which gives the shampoo-conditioner a suitable washout and flow behaviorleaving the hair in good condition.

Specific ivermectin concentrations tested, as shown in Example 1,include 0.25%, 0.50% and 1.00% ivermectin. This concentration range,shown in Example 1 to effectively kill permethrin-resistant head lice,is presented to simply exemplify the invention and in no way limit theeffective range that may be utilized by the artisan to practice theclaimed invention. As noted above in this detailed description of theinvention section, the artisan may choose an appropriate range ofivermectin (measured as weight/volume [w/v]) anywhere in the range fromabout 0.005% to about 5%.

Of course, the w/v ratio of the formulation may be adjusted to take intoaccount differing amounts of ivermectin on a g/l basis. Adjustments mayeasily be incorporated with components, known equivalent components,combination of components, and respective concentrations to provide foralternative avermectin- or ivermectin-based formulations for usesdisclosed herein.

Thus, the artisan will be aware that the percentage by weight of anycomponent may be adjusted to compensate for the concentration of theactive ingredient, the texture of the topical formulation (e.g.,shampoo, cream, gel) and that components may be added at differingconcentrations or may be left out of a formulation or substituted withan equivalent component so as to provide for an avermectin- orivermectin-based topical formulation which possesses efficacy againsttreatment-resistant strains of head, pubic or body lice similar to theexemplified topical formulation described herein.

TABLE 1 Ingredient % (by weight) Ivermectin 0.5 Deionized Water 33 OliveOil USP 27.75 Polysorbate 80 (and) 11.75 Cetyl Acetate (and) 3.0Acetylated .25 Lanolin Alcohol Oleyl Alcohol 10 Lanolin Alcohol 8Cyclomethicone 3 Shea Butter 2 Sorbitan Tristearate 0.5 Methylparaben0.2 Propylparaben 0.05

A person of the ordinary skill in the art will appreciate that otherbeneficial agents can be added into a formula of the instant invention.Such beneficial agents include, without limitation, vitamins, hair dyes,nutrients, anti-dandruff agents and the like.

A person of the ordinary skill will have sufficient expertise toproperly select the beneficial agent or the combination thereofdepending on the specific embodiment of the invention, so that the atleast one beneficial agent would not negate the beneficial aspects ofthe formula.

One of ordinary skill in the art would appreciate that the formulationand method described herein for eliminating treatment resistant lice isnot meant to be a limiting disclosure, but only gives a preferredembodiment of the invention.

EXAMPLE 1 Formulation and Testing of Ivermectin Shampoo-Conditioner onPermethrin Resistant Head Lice

Having described the invention in general terms, the following specificexample is offered for purposes of illustration and for illustrationonly, and no intention to limit the invention is to be inferredtherefrom. A pediculicide containing ivermectin as a topicalshampoo-conditioner for eliminating treatment resistant lice may beprepared as follows.

Preparing the Formulation

The formulation shown in Table 1 may be made by the followingnon-limiting example. The 0.50% w/v of the active ingredient(ivermectin) is pre-dissolved in a vessel containing surfactants,hereinafter Phase A, consisting of 11.75% w/v of polysorbate 80, 3% w/vof cetyl acetate, and 0.25% w/v of acetylated lanolin alcohol. Phase Ais heated, with mixing, at a constant temperature of 65° C. until theactive ingredient is completely dissolved in the surfactants. Phase A isthen transferred into a vessel containing Phase B, wherein Phase Bconsists of suspending agents, preservatives, non-ionic surfactants,humectants, and a conditioner agent.

Phase B may consist of 27.75% w/v of olive oil, 2% w/v of shea butter,8% w/v of lanolin alcohol, 3% w/v of cyclomethicone, 0.50% w/v ofsorbitan triesterate, 0.20% w/v of methyl paraben, and 0.05% w/v ofpropyl paraben. Phase B combined with Phase A are heated, with mixing,at a constant temperature of about 85° C. until all ingredients aredissolved and/or melted. Concurrently, Phase C, consisting of water, isheated at a constant temperature of about 85° C. With vigorous mixing,Phase A/B is slowly transferred into Phase C. Continue mixing theformulation at or near room temperature until the desired formulationconsistency is obtained and subsequently package the formulation.

Formulated Ivermectin Concentrations

The present invention may be prepared in concentrations of 1%, 0.5%, and0.25% of ivermectin in a formulation containing deionized water, oliveoil USP, surfactants, shea butter, sorbitan tristearate, methylparaben,and propylparaben. For comparison purposes, a Nix® formulation (Pfizer,Morris Plains, N.J.) containing 1% permethrin (v/v), an Ovide®formulation (Medicis, Phoenix, Ariz.) containing 0.5% malathion (v/v), anon-formulated ivermectin solution (Chem Service Inc., West Chester,Pa.), a placebo formulation (ivermectin formulation sans ivermectin) anddistilled, deionized water (ddH₂O) are used as positive (Nix®, Ovide®and non-formulated ivermectin), negative (placebo), and no treatment(ddH2O) controls.

Selection of Human Head Lice

The SF-HL strain of permethrin-resistant human head lice (Pediculushumanus capitis, Phthiraptera:Pediculidae) is collected from infestedchildren in Plantation and Homestead, Fla. and is maintained on an invitro feeding system at the University of Massachusetts at Amherst,Mass. as described by Yoon et al. (2006). Lice are maintained without ahuman host on the in vitro rearing system from about 24 to about 36generations. Permethrin-resistant SF-HL are selected periodically using1% permethrin-treated filter papers (Yoon et al. 2006). Filter papers(35 mm diameter, Whatman No. 1) are immersed into 1% permethrindissolved in acetone (w/v) for 10 seconds and is air dried in a darkfumehood from about 20 to about 30 minutes. Mixed developmental stages(first instars to adult) are placed on the treated filter paper andexposed for about 5 hours. Surviving lice are transferred back into thefeeding system. The SF-HL strain are susceptible to Ovide® (0.5%malathion), but resistant to Nix® (1% permethirn) and cross-resistant toDDT treatments. (Yoon et al. 2003).

Bioassays

Mortality bioassays are performed to compare lethal time to 50%mortality values (LT₅₀) between the ivermectin formulations, Nix®, andOvide®. Experimental lice are newly hatched first instars (less than 24hours old). The lice are randomly taken from the in vitro rearingsystem, where the lice take an overnight blood meal. Lice (about 30lice/treatment) are placed on an individual hair tuft (about 300strands, about 4 cm in length) using sterile forceps, and the treatmentis gently rubbed into the hair until saturation occurs.

After a 10 minute exposure period, the hair tuft with lice are washedsequentially in three separate water baths, containing about 10 ml ofddH2O for about 5 seconds each. The washed hair tuft with lice isblotted onto stacks of filter paper and air dried for about 5 minutes.Any lice dislodged during treatment or washing are placed back onto thetreated hair tuft. After drying, the treated hair tuft with lice isexamined under a dissecting microscope and the number of dead lice isrecorded.

A louse is considered dead if it can not right itself when inverted andwhen its legs have ceased all movements when probed. Treated hair tuftswith lice are then placed onto the feeding membrane in the in vitrorearing system and are maintained at 31° C. and 75% humidity. Thenumbers of dead lice are reassessed at 10 minute intervals until agreater than 90% mortality is achieved. The timing for mortality beginsimmediately following the 10 minute exposure period. Because of this,mortality is not assessed during the washing and drying intervals (about5 minutes). Log time versus logit percent mortality regression lines aregenerated to determine LT₅₀ and LT₉₅ values and maximum log-likelihoodratio tests are performed to test the equality (slope and intercept) ofthe regression lines (p<0.05, Polo PC, LeOra Software, 1987).

To determine whether ivermectin in formulation performs better thanivermectin alone, blood-fed lice are placed onto 0.5% (w/v) ivermectinformulation-treated hair tufts as described above. Blood-fed lice arealso placed onto hair tufts that are treated with 0.5% ivermectin inacetone (acetone is allowed to volatilize in a fumehood for about 1 hourprior to transferring lice to the treated hair tuft), washed, andtransferred to the in vitro rearing system as described above.

SF-HL Lice Mortality Response to Ivermectin Formulations

The mortality responses of the SF-HL lice strain following a 10 minuteexposure to all three ivermectin formulations (1%, 0.5%, and 0.25%) aresignificantly different compared to SF-HL lice exposed only to ddH2O(χ²=90.1, df=2, P<0.001; χ²=199.5, df=2, P<0.001, χ²=213.5, df=2,P<0.001), respectively (FIG. 3). At the LT₅₀ and LT₉₅ following a 10minute exposure, the 1% ivermectin formulation is 426 and 491 timesfaster than the ddH2O treatments, respectively (Table 2).

TABLE 2 Comparison of median lethal time (LT₅₀ and LT₉₅, followingexposures of the SF-HL lice strain to the ivermectin formulations).Slope values are determined from log time versus logit mortalityregression lines, which are obtained using the hair tuft bioassay of thepermethrin-resistant (SF-HL) and permethrin-susceptible (EC-HL) headlouse populations. Populations are treated with the formulations, Nix ®,and Ovide ®. Reject LT₅₀ LT₉₅ null Treatment (CL) ^(a) (CL) ^(a) Slopehypothesis ^(b) 1% 50.4 88.0 12.1 ± 1.7  + (46.5- (78.7- 54.1) 104.5)0.5% 58.1 130.4 8.4 ± 1.0 + (52.9- (113.8- 63.0) 158.7) 0.5% (5 min 93.7196.7 8.5 ± 1.1 + exposure) (82.9- (168.8- 103.6) 249.1) 0.5% (3 min204.7 426.4 10.5 ± 1.5  + exposure) (176.7- (359.3- 236.8) 556.7) 0.25%119.3 208.9 12.1 ± 1.5  + (112.7- (189.2- 125.9) 241.5) 0.5% (non- 221.8419.4 10.6 ± 1.5  + formulated) (204.5- (363.9- 238.5) 532.5) Placebo4.8 days 24 days 3.3 ± 0.4 + (formulation (3.6- sans 6.2) ivermectin)Nix ® ^(c) 4.3 days >15 days   2.1 ± 0.17 + (3.9- 4.8) Nix ® (EC-HL)^(d) 177.7 357.0 9.7 ± 1.8 + (126.1- (282.7- 223.3) 628.6) ddH₂O 14.9days  30 days 3.1 ± 0.5 + (12.0- 18.8) Ovide ® ^(e) <5.0 <5.0 — + ^(a)CL, 95% confidence interval limit. ^(b) The null hypothesis tests forequality of the slope and intercept of the regressions (p < 0.05) (seemaximum log-likelihood ratio test in text). ^(c) Nix ® LT₅₀ values forSF-HL and EC-HL are from historical data previously determined using thesame experimental bioassay (Yoon et al. 2006). ^(d) EC-HL arepermethrin-susceptible lice collected from Kuna Indians in Ecuador. ^(e)LT₅₀ and LT₉₅ values following Ovide ® treatments are estimated timessince log time versus logit mortality responses curves were notgenerated given the fast response times (see methods section).

At the LT₅₀ and LT₉₅ following a 10 minute exposure, the 0.5% ivermectinformulation is 369 and 331 times faster than the ddH₂O treatments,respectively, and the 0.25% ivermectin formulation is 180 and 207 timesfaster than the ddH2O treatments, respectively (Table 2). The mortalityresponse to the non-formulated 0.5% ivermectin treatment issignificantly different compared to ddH2O (χ²=168.1, df=2, P<0.001)(FIG. 1). At the LT₅₀ and LT₉₅ following a 10 minute exposure,non-formulated 0.5% ivermectin is 96.7 and 103.0 times faster than ddH2Otreatment, respectively (Table 2).

Ivermectin as Compared to Placebo

The mortality responses for all three of the ivermectin formulations aresignificantly different compared to the placebo formulation (χ²=157.5,df=2, P<0.001; χ²=178.8, df=2, P<0.001; χ²=190.0, df=2, P<0.001,respectively). At the LT₅₀ and LT₉₅ following a 10 minute exposure, the1% ivermectin formulation is 137 and 393 times faster than placeboformulation, respectively (Table 2). At the LT₅₀ and LT₉₅ following a 10minute exposure, the 0.5% ivermectin formulation is 119 and 265 timesfaster than the placebo formulation, respectively. At the LT₅₀ and LT₉₅following a 10 minute exposure, the 0.25% ivermectin formulation is 58and 165 times faster than the placebo formulation, respectively (Table2).

The mortality response to non-formulated 0.5% ivermectin issignificantly different compared to the placebo formulation (χ²=143.8df=2, P<0.001). At the LT₅₀ and LT₉₅ following a 10 minute exposure,non-formulated 0.5% ivermectin is 31.2 and 82.4 times faster thanplacebo treatment, respectively (Table 2).

Ivermectin as Compared to Nix®

The mortality responses for all three of the ivermectin formulations aresignificantly different compared to the Nix® (χ²=211.8, df=2, P<0.001;χ²=244.0, df=2, P<0.001; χ²==244.0, df=2, P<0.001), respectively (FIG.3). At the LT₅₀ and LT₉₅ following a 10 minute exposure, the 1%ivermectin formulation is 123 and 245 times faster than Nix®,respectively (Table 2). At the LT₅₀ and LT₉₅ following a 10 minuteexposure, the 0.5% ivermectin formulation is 107 and 166 times fasterthan Nix®, respectively. At the LT₅₀ and LT₉₅ following a 10 minuteexposure, the 0.25% ivermectin formulation is 52 and 103 times fasterthan Nix®, respectively (Table 2). The mortality response tonon-formulated 0.5% ivermectin is significantly different compared toNix® (χ²=180.6 df=2, P<0.001). At the LT₅₀ and LT₉₅ following a 10minute exposure, non-formulated 0.5% ivermectin is 27.9 and 51.5 timesfaster than Nix®, respectively (Table 2).

The mortality responses for all three of the ivermectin formulations aresignificantly different compared to non-formulated 0.5% ivermectin(χ²=143.8, df=2, P<0.001; χ²=153.2, df=2, P<0.001; χ²=100.3, df=2,P<0.001, respectively (FIG. 3). At the LT₅₀ and LT₉₅ following a 10minute exposure, the 1% ivermectin formulation is 4.4 and 4.8 timesfaster than non-formulated 0.5% ivermectin (Table 2). At the LT₅₀ andLT₉₅ following a 10 minute exposure, the 0.5% ivermectin formulation is3.8 and 3.2 times faster than the 0.5% non-formulated ivermectin,respectively. At the LT₅₀ and LT₉₅ following a 10 minute exposure, the0.25% ivermectin formulation is 1.9 and 2.0 times faster thannon-formulated 0.5% ivermectin, respectively (Table 2).

Mortality Response of 1% Ivermectin Formulation as Compared to 0.5% and0.25% Ivermectin Formulations

The mortality response for the 1% ivermectin formulation issignificantly different from that produced by the 0.5% and the 0.25%formulations following 10 minute exposures (χ²=11.5, df=2, P=0.003,χ²==134.8, df=2, P=0.001, respectively) (FIG. 3). At the LT₅₀ and LT₉₅following a 10 minute exposure, the 1% ivermectin formulation is 1.2 and1.5 times faster than the 0.5% ivermectin formulation, respectively(Table 1). At the LT₅₀ and LT₉₅ following a 10 minute exposure, the 1%ivermectin formulation is 2.4 and 2.4 times faster than the 0.25%ivermectin formulation, respectively (Table 2).

The mortality response for the 0.5% ivermectin formulation issignificantly different than that produced by the 0.25% formulationfollowing a 10 minute exposure (χ²=121.5, df=2, P<0.001) (FIG. 1). Atthe LT₅₀ and LT₉₅ following a 10 minute exposure, the 0.5% ivermectinformulation is 2.0 and 1.6 times faster than the 0.25% ivermectinformulation, respectively (Table 2).

Mortality Response Following 5 and 3 Minute Exposure of the 1% and 0.5%Ivermectin Formulations

The mortality response for the 1% ivermectin formulation following a 10minute exposure is significantly different compared to the 0.5%ivermectin formulation with a 5 minute exposure and the 0.5% ivermectinformulation with a 3 minute exposure (χ²=80.6f=2, P<0.001, χ²=163.3,df=2, P<0.001), respectively. At the LT₅₀ and LT₉₅, the 1.0% ivermectinformulation following a 10 minute exposure is 1.9 and 2.2 times fasterthan the 0.5% ivermectin formulation with a 5 minute exposure,respectively (Table 2).

At the LT₅₀ and LT₉₅, the 1.0% ivermectin formulation following a 10minute exposure is 4.1 and 4.9 times faster than the 0.5% ivermectinformulation with a 3 minute exposure, respectively (Table 2). Themortality response for the 0.5% ivermectin formulation following a 10minute exposure is significantly different compared to the 0.5%formulation with a 5 minute exposure and the 0.5% ivermectin formulationwith a 3 minute exposure (χ²=55.1, df=2, P<0.001, χ²=175.2, df=2,P<0.001), respectively. At the LT₅₀ and LT₉₅, the 0.5% ivermectinformulation with a 10 minute exposure is 1.6 and 1.5 times faster thanthe 0.5% ivermectin formulation with a 5 minute exposure, respectively(Table 2). At the LT₅₀ and LT₉₅, the 0.5% ivermectin formulationfollowing a 5 minute exposure is 3.5 and 3.3 times faster than the 0.5%ivermectin formulation with a 3 minute exposure, respectively (Table 2).

The mortality response for the 0.25% ivermectin formulation following a10 minute exposure is significantly different from that produced by the0.5% formulation with a 5 minute exposure and the 0.5% ivermectinformulation with a 3 minute exposure (χ²=25.6, df=2, P<0.001, χ²=95.0,df=2, P<0.001), respectively (FIG. 3). At the LT₅₀ and LT₉₅, the 0.25%ivermectin formulation following a 10 minute exposure is 1.3 and 1.1times slower than the 0.5% ivermectin formulation with a 5 minuteexposure, respectively (Table 2). At the LT₅₀ and LT₉₅, the 0.25%ivermectin formulation following a 10 minute exposure is 1.7 and 2.0times faster than the 0.5% formulation with a 3 minute exposure,respectively (Table 2).

The mortality response for the 0.5% formulation with a 5 minute exposureis significantly different compared to the 0.5% formulation with a 3minute exposure (χ²=118.8, df=2, P<0.001). At the LT₅₀ and LT₉₅, the0.5% formulation with a 5 min exposure is 2.2 and 2.2 times faster thanthe 0.5% formulation with a 3 min exposure, respectively (Table 1).

Ivermectin Formulation Results Summary

Treatments with 1%, 0.5% and 0.25% ivermectin formulations result in asignificantly faster mortality response than treatments with placebo orddH2O, indicating that the present invention is pediculicidal onpermethrin-resistant head lice. Ivermectin formulations have a fastermortality response than Nix® treatments indicating that the ivermectinformulation of the present invention is a faster acting pediculicide.The 1% ivermectin formulation works significantly faster than its 0.5%formulation and the 0.5% formulation works significantly faster than its0.25% formulation.

The 0.5% ivermectin formulation with a 10 minute exposure workssignificantly faster than the 0.5% formulation with a 5 minute exposureand both are significantly faster than the 0.5% formulation with a 3minute exposure.

However, the non-formulated 0.5% ivermectin solution is 3.2 to 3.8 timesslower at killing SF-HL than the 0.5% ivermectin formulation of thepresent invention. The exact reason for the superior killing power ofivermectin in formulation may be due to the increased penetration, orincreased transfer, of the active ingredient residues to louse cuticles.

Nix® is not 100% effective at killing treated SF-HL using the hair tuftbioassay system (Yoon et al. 2006). All ivermectin formulationsdisclosed herein kills 100% of SF-HL lice.

Development of Lice on Substrates Treated with Ivermectin

A nit of head lice normally undergoes a 7-9 day incubation beforehatching as a baby nymph. It looks like an adult head louse, but issmaller. Nymphs mature into adults about 7 days after hatching. To live,the nymph must feed on blood. It metamorphoses 3 times before it reachesthe adult stage.

During the experiments, including those described above, it was observedthat the eggs incubated on substrates treated with the compositions ofthe instant invention were able to hatch into first instar nymphs butthen all died. It is indirectly ovicidal. This mode of action isdifferent from the mode of action of permethrin. It was also observedthat but the nymphs died almost immediately after hatching. Therefore,these observations demonstrate that the compositions of the instantpenetrates the egg and the invention are efficient at least for 7-9 days(i.e., the time needed for incubation of the eggs)

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A topical formulation comprising: an effectiveamount of dissolved ivermectin; about 20% to about 35% by weight oliveoil; about 1% to about 5% by weight shea butter; nonionic surfactantscomprising oleyl alcohol, sorbitan tristearate, and lanolin alcohol; asolubilizing agent comprising cetyl acetate, polysorbate 80, andacetylated lanolin alcohol; about 0.01% to about 2% by weightmethylparaben; about 0.01% to about 0.5% by weight propylparaben; about1% to about 5% by weight of a conditioner comprising cyclomethicone; andabout 30% to about 40% by weight water.
 2. The formulation of claim 1,wherein the formulation does not include any glycols.
 3. The formulationof claim 1, wherein the formulation comprises below 5% by weight of aglycol.
 4. The formulation of claim 1, wherein the olive oil is presentin an amount of about 27.5% by weight of the formulation.
 5. Theformulation of claim 1, wherein the ivermectin is present in an amountof about 0.25% to about 1% by weight of the formulation.
 6. Theformulation of claim 1, wherein the formulation is formulated as acream, gel, pomade, shampoo-conditioner, cream rinse or lotion.
 7. Theformulation of claim 6, wherein the formulation is formulated as acream.
 8. The formulation of claim 1, wherein the formulation is for usein the prophylactic or therapeutic treatment of a head lice infestationin a human.
 9. The formulation of claim 1, wherein the formulation isindirectly ovicidal.
 10. The formulation of claim 1, wherein theformulation has a volume of about 1 mL to about 100 mL and contains aunit dose of ivermectin.
 11. The formulation of claim 1, wherein theformulation comprises oleyl alcohol and lanolin alcohol at a combinedconcentration of about 10% to about 35% by weight.
 12. The formulationof claim 1, wherein the formulation comprises oleyl alcohol and lanolinalcohol at a combined concentration of about 18% to about 24% by weight.13. The formulation of claim 1, wherein the formulation comprises about5% to about 15% by weight oleyl alcohol.
 14. The formulation of claim 1,wherein the formulation comprises about 3% to about 15% by weightlanolin alcohol.
 15. The formulation of claim 1, wherein the formulationcomprises about 5% to about 10% by weight lanolin alcohol.
 16. Theformulation of claim 1, wherein the formulation comprises about 0.1% toabout 3% by weight sorbitan tristearate.
 17. The formulation of claim 1,wherein the formulation comprises about 0.5% to about 10% by weightcetyl acetate.
 18. The formulation of claim 1, wherein the formulationcomprises about 1% to about 4% by weight cetyl acetate.
 19. Theformulation of claim 1, wherein the formulation comprises about 5% toabout 25% by weight polysorbate
 80. 20. The formulation of claim 1,wherein the formulation comprises about 10% to about 15% by weightpolysorbate
 80. 21. The formulation of claim 1, wherein the formulationcomprises about 0.10% to about 3% by weight acetylated lanolin alcohol.22. The formulation of claim 1, wherein the formulation comprises about0.5% to about 1% by weight acetylated lanolin alcohol.
 23. Theformulation of claim 1, wherein the ivermectin is present in an amountof about 0.05% to about 5% by weight of the formulation.
 24. Theformulation of claim 1, wherein the olive oil is present in an amount ofabout 20% to about 30% by weight of the formulation.
 25. The formulationof claim 1, wherein the olive oil is present in an amount of about 25%to about 28% by weight of the formulation.